Th17 Pathway Plasticity in the Pathogenesis of Inflammatory Bowel Disease. The Th17 subset has been implicated in a number of immune-mediated diseases, including IBD. Despite the acknowledged importance of the Th17/IL-23 axis in intestinal inflammation, questions remain regarding stability of the Th17 lineage and the role of IFN-? in colitis pathogenesis. In human and mouse colitis, T cells that express either IL-17A or IFN-?, or both are found in inflamed intestinal tissues. In published studies we have found using novel cytokine reporter mice that Th17 cells show late developmental plasticity, such that under the influence of IL-23, Th17 cells can deviate to IFN-?+ cells (`Th1-like' cells) in a mannr that is dependent on the transcription factors Stat4 and T-bet. Our new preliminary data show that Th17 cells deficient in Stat4 or T-bet are impaired in their transition to IFN-?+ cells in vvo, and their colitogenic potential is markedly reduced. Similarly, Th17 cells that are deficient in IFN-? do not induce colitis. We hypothesize that IL-17A and IFN-? producing cells arise from common Th17 precursors under the influence of IL-23 and have distinct roles in IBD pathogenesis: IFN-?+ Th1-like cells are required for disease development whereas mature Th17 cells that express only IL-17A are protective. In this proposal we will explore how late diversity n Th17 differentiation impacts IBD development by using recently created IL-17A reporter mice to (i) study the contribution of Th17-derived IL-17A+ and IFN-?+ cells to the development of colitis and (ii) define mechanisms by which Th1-like cells derived from the Th17 pathway drive intestinal inflammation.